Developmental disorders of the human cerebral cortex underlie 15-40% of cases of epilepsy, especially intractable pediatric epilepsy. Hence, a powerful genetic approach to the understanding of these epilepsies, as well as to the study of cerebral cortical development, relies upon the identification of the causative genes in disorders of neuronal migration. Recent work from our lab and simultaneous work from other labs has identified mdab1, a murine homologue of Drosophila disabled (dab), as the gene mutated in the scrambler mouse. Moreover, we have recently discovered a novel gene, doublecortin (DCX), that is mutated in patients with the double cortex/X-linked lissencephaly syndrome, DC/XLIS, and that Filamin-1 mutations in humans cause another migrational disorder, periventricular heterotopia. Since these predicted proteins appear to lack intrinsic enzymatic activity, their cellular mechanism of action is not obvious, and they likely act via protein-protein interactions with other, as yet unidentified proteins. The overall goal of this proposal is to analyze the cellular role of mDab1 and FLN1 in neuronal migration, and their relationship to the previously identified DCX and LIS1 genes which are mutated in human lissencephaly. Specific aim 1 will screen PH patients for mutations in FLN1 and correlate the positions of mutations with the predicated structure of FLN1 and correlate the positions of mutations with the predicted structure of FLN1 protein and the severity of clinical phenotypes This should help identify amino acid residues critical for FLN1 function and potential functional motifs This should help identify amino acid residues critical for FLN1 function and potential motifs of the protein. Specific aim 2 will determine the pattern of expression of FLN1 mRNA and protein, in order to test hypotheses about where and when the protein is required. Specific aim 3 will analyze the potential phosphorylation of DCX by Abl, and identify protein-protein interactions between Abl, mDabl, FLN1, DCX, and LIS1, because of evidence that DCX and mDab1 form part of a signaling pathway that relies on the tyrosine kinase c-Abl. Specific aim 4 will create an animal model that play critical roles in guiding migrating neurons, and these additional genes will be candidate genes for other human disorders of cerebral cortical development.